Abstract Autism is a behaviourally defined disorder including attenuated or abnormal social interaction and communication, as well as aberrant repetitive behaviour, with symptoms emerging early in childhood. Although the cause of autism has not been discovered, several data strongly support the role of genetic factors in autism aetiology. For this reason, preclinical research is now focusing on generating transgenic and knockout mice, and more recently also rats, with mutations in genes identified in autistic children, with the main aim of understanding the role of those genes in autism aetiology, discovering the biological mechanisms underlying autistic behaviours detected in these mutant lines and evaluating potential treatments. Over the last years, a huge number of behavioural phenotyping assays for rodent models of autism and related disorders have been designed. In the first part of our review, we focus on current standards, i.e. state-of-the-art behavioural phenotyping tasks to assess autism core symptoms in rodent models. The second part is devoted to some few, in our view, very promising examples of new developments, namely an autism severity score, scent marking behaviour as an additional, ethologically valid measure for communication, plus a number of new developments in the behavioural domains of social facilitation, observational learning, and empathy. Finally, we will highlight the huge potential impact of newly generated rat knockout models of autism.

Abstract Early childhood autism is characterized by deficits in social approach and play behaviors, socio-emotional relatedness, and communication/speech abnormalities, as well as repetitive behaviors. These core neuropsychological features of autism can be modeled in laboratory rats, and the results may be useful for drug discovery and therapeutic development. We review data that show that rats selectively bred for low rates of play-related pro-social ultrasonic vocalizations (USVs) can be used to model social deficit symptoms of autism. Low-line animals engage in less social contact time with conspecifics, show lower rates of play induced pro-social USVs, and show an increased proportion of non-frequency modulated (i.e. monotonous) ultrasonic vocalizations compared to non-selectively bred random-line animals. Gene expression patterns in the low-line animals show significant enrichment in autism-associated genes, and the NMDA receptor family was identified as a significant hub. Treatment of low-line animals with the NMDAR functional glycine site partial agonist, GLYX-13, rescued the deficits in play-induced pro-social 50-kHz USVs and reduced monotonous USVs. Since the NMDA receptor has been implicated in the genesis of autistic symptoms, it is possible that GLYX-13 may be of therapeutic value in the treatment of autism.

Autism spectrum disorders (ASD) form a common group of neurodevelopmental disorders appearing to be under polygenic control, but also strongly influenced by multiple environmental factors. The brain mechanisms responsible for ASD are not understood and animal models paralleling related emotional and cognitive impairments may prove helpful in unraveling them. BTBR T+tf/J (BTBR) mice display behaviors consistent with the three diagnostic categories for ASD. They show impaired social interaction and communication as well as increased repetitive behaviors. This review covers much of the data available to date on BTBR behavior, neuroanatomy and physiology in search for candidate biomarkers, which could both serve as diagnostic tools and help to design effective treatments for the behavioral symptoms of ASD.

Autism is a neurodevelopmental disorder characterized by social and communication impairments and repetitive behaviours. The inbred BTBR T+tf/J (BTBR) strain, a putative mouse model of autism, exhibits lower social interactions, higher repetitive self-grooming levels and unusual pattern of vocalizations as compared to C57BL/6J strain. First aim of the present study was to evaluate at adolescence (postnatal days 30–35) male BTBR and C57BL/6J performances in two different tasks involving either investigation of social cues (same strain partners) or non social ones (inanimate objects). In the social interaction test, BTBR mice showed a reduction of investigation of the social partner, due to a selective reduction of head sniffing, associated with a decrease in ultrasonic vocalizations. By contrast, no strain differences were detected in object investigations. Second aim of the study was to evaluate adult male BTBR and C57BL/6J performances in a fear conditioning task. Strain differences were evident during contextual retest : these strain differences primarily suggested a lack of behavioural flexibility in BTBR mice (i.e. realizing the occurrence of changes in the experimental paradigm). Subsequent electrophysiological analysis in hippocampal slices from adult BTBR and C57BL/6J mice revealed a significant reduction of Brain Derived Neurotrophic Factor (BDNF)-induced potentiation of synaptic transmission in BTBR mice. BDNF and tyrosine kinase B (TrkB) protein levels measured in the hippocampal region were also lower in BTBR as compared to C57BL/6J mice. These data confirm the presence of low levels of direct interaction with social stimuli in BTBR mice at adolescence, in the absence of any strain difference as for investigation of physical objects. At adulthood in BTBR mice clear signs of behavioural inflexibility were evident whereas both biochemical and electrophysiological data point to decreased BDNF signalling (likely due to a reduction in TrkB levels) in the hippocampus of this mouse strain.

Autism is the short name of a complex and heterogeneous group of disorders (autism spectrum disorders, ASD) with several lead symptoms required for classification, including compromised social interaction, reduced verbal communication and stereotyped repetitive behaviors/restricted interests. The etiology of ASD is still unknown in most cases but monogenic heritable forms exist that have provided insights into ASD pathogenesis and have led to the notion of autism as a ‘synapse disorder’. Among the most frequent monogenic causes of autism are loss-of-function mutations of the NLGN4X gene which encodes the synaptic cell adhesion protein neuroligin-4X (NLGN4X). We previously described autism-like behaviors in male Nlgn4 null mutant mice, including reduced social interaction and ultrasonic communication. Here, we extend the phenotypical characterization of Nlgn4 null mutant mice to both genders and add a series of additional autism-relevant behavioral readouts. We now report similar social interaction and ultrasonic communication deficits in females as in males. Furthermore, aggression, nest-building parameters, as well as self-grooming and circling as indicators of repetitive behaviors/stereotypies were explored in both genders. The construction of a gender-specific autism severity composite score for Nlgn4 mutant mice markedly diminishes population/sample heterogeneity typically obtained for single tests, resulting in p values of <0.00001 and a genotype predictability of 100% for male and of >83% for female mice. Taken together, these data underscore the similarity of phenotypical consequences of Nlgn4/NLGN4X loss-of-function in mouse and man, and emphasize the high relevance of Nlgn4 null mutant mice as an ASD model with both construct and face validity.

Mutations in neurexin and neuroligin genes have been associated with neurodevelopmental disabilities including autism. Autism spectrum disorder is diagnosed by aberrant reciprocal social interactions, deficits in social communication, and repetitive, stereotyped patterns of behaviors, along with narrow restricted interests. Mouse models have been successfully used to study physiological and behavioral outcomes of mutations in the trans-synaptic neurexin–neuroligin complex. To further understand the behavioral consequences of Neuroligin2 (NLGN2) mutations, we assessed several behavioral phenotypes relevant to autism in neuroligin2 null (Nlgn2−/−), heterozygote (Nlgn2+/−), and wildtype (Nlgn2+/+) littermate control mice. Reduced breeding efficiency and high reactivity to handling was observed in Nlgn2−/− mice, resulting in low numbers of adult mice available for behavioral assessment. Consistent with previous findings, Nlgn2−/− mice displayed normal social behaviors, concomitant with reduced exploratory activity, impaired rotarod performance, and delays on several developmental milestones. No spontaneous stereotypies or repetitive behaviors were detected. Acoustic, tactile, and olfactory sensory information processing as well as sensorimotor gating were not affected. Nlgn2−/− pups isolated from mother and littermates emitted fewer ultrasonic vocalizations and spent less time calling than Nlgn2+/+ littermate controls. The present findings add to the growing literature on the role of neurexins and neuroligins in physiology and behavior relevant to neurodevelopmental disorders.

Several synaptic genes predisposing to autism-spectrum disorder (ASD) have been identified. Nonsense and missense mutations in the SYN1 gene encoding for Synapsin I have been identified in families segregating for idiopathic epilepsy and ASD and genetic mapping analyses have identified variations in the SYN2 gene as significantly contributing to epilepsy predisposition. Synapsins (Syn I/II/III) are a multigene family of synaptic vesicle-associated phosphoproteins playing multiple roles in synaptic development, transmission and plasticity. Lack of SynI and/or SynII triggers a strong epileptic phenotype in mice associated with mild cognitive impairments that are also present in the non-epileptic SynIII−/− mice. SynII−/− and SynIII−/− mice also display schizophrenia-like traits, suggesting that Syns could be involved in the regulation of social behavior. Here, we studied social interaction and novelty, social recognition and social dominance, social transmission of food preference and social memory in groups of male SynI−/−, SynII−/− and SynIII−/− mice before and after the appearance of the epileptic phenotype and compared their performances with control mice. We found that deletion of Syn isoforms widely impairs social behaviors and repetitive behaviors, resulting in ASD-related phenotypes. SynI or SynIII deletion altered social behavior, whereas SynII deletion extensively impaired various aspects of social behavior and memory, altered exploration of a novel environment and increased self-grooming. Social impairments of SynI−/− and SynII−/− mice were evident also before the onset of seizures. The results demonstrate an involvement of Syns in generation of the behavioral traits of ASD and identify Syn knockout mice as a useful experimental model of ASD and epilepsy.

Autism is a pervasive disorder characterized by a complex symptomatology, based principally on social dysfunction. The disorder has a highly complex, largely genetic etiology, involving an impressive variety of genes, the precise contributions of which still remain to be determined. For this reason, a reductionist approach to the study of autism has been proposed, employing monogenic animal models of social dysfunction, either by targeting a candidate gene, or by mimicking a single-gene disorder characterized by autistic symptoms. In the present review, we discuss this monogenic approach by comparing examples of each strategy : the mu opioid receptor knock-out (KO) mouse line, which targets the opioid system (known to be involved in the control of social behaviors) ; and the Fmr1-KO mouse, a model for Fragile X syndrome (a neurodevelopmental syndrome that includes autistic symptoms). The autistic-relevant behavioral phenotypes of the mu-opioid and Fmr1-KO mouse lines are described here, summarizing previous work by our research group and others, but also providing novel experimental evidence. Relevant factors influencing the validity of the two models, such as sex differences and age at testing, are also addressed, permitting an extensive evaluation of the advantages and limits of monogenic mouse models for autism.

Autism spectrum disorders (ASD) and social anxiety disorder involve various forms of social deficits like impaired affiliative behavior, social cognition and social approach. Although the neurobiological underpinnings of these disorders are largely unknown, rodent and human studies suggest an involvement of the evolutionary highly conserved oxytocin (OXT) and vasopressin (AVP), as these neuropeptides modulate various aspects of mammalian social behaviors. In this review we summarize the current knowledge regarding the involvement of brain OXT and AVP in rodent social behaviors related to social dysfunctions in ASD. Starting with an introduction into the neurobiology of the central OXT and AVP systems (neuroanatomy, central release, receptor distribution) we describe the distinct roles OXT and AVP play in basic social behaviors in rodents, i.e. affiliative behavior (pair-bonding and maternal behavior), social cognition (social memory), and social approach (social preference or social avoidance). The regulatory capacity of OXT and AVP to modulate social behaviors in various rodent species implies a high translational potential, in particular that dys-regulations in the brain neuropeptide systems may underlie social dysfunctions in ASD. It also suggests that the brain OXT and AVP systems are promising pharmacotherapeutic targets to improve social behaviors and to reverse social deficits.

Abstract Autism spectrum disorder (ASD) is a severe neuropsychiatric disease with strong genetic underpinnings. However, genetic contributions to autism are extremely heterogeneous, with many different loci underlying the disease to a different extent in different individuals. Moreover, the phenotypic expression (i.e., “penetrance”) of these genetic components is also highly variable, ranging from fully penetrant point mutations to polygenic forms with multiple gene–gene and gene–environment interactions. Furthermore, many genes involved in ASD are also involved in intellectual disability, further underscoring their lack of specificity in phenotypic expression. We shall hereby review current knowledge on the genetic basis of ASD, spanning genetic/genomic syndromes associated with autism, monogenic forms due to copy number variants (CNVs) or rare point mutations, mitochondrial forms, and polygenic autisms. Finally, the recent contributions of genome-wide association and whole exome sequencing studies will be highlighted.

Autism Spectrum Disorder (ASD) is by definition a complex and heterogeneous disorder. Variation in factors such as developmental level, language ability and IQ further complicate the presentation of symptoms. Clinical research and basic science must continue to inform each other’s questions to help address the heterogeneity inherent to the disorder. This review uses a clinical perspective to outline the common tools and best practices for diagnosing and characterizing ASD in a research setting. We discuss considerations for classifying research populations, including language ability and IQ and examine the advantages and disadvantages of different psychometric measurements. Ultimately, the contribution of multiple sources of data representing different perspectives is crucial for interpreting and understanding the ASD phenotype.

Recent discoveries and advances in genetics and neuroscience have provided deeper understanding of the complex neurobiology of ASD. The development of novel treatments is strictly dependent on these findings in order to design new strategies in the pharmacotherapy of ASD. At this time, therapeutics are limited to treating associated core, symptoms. Studies of single gene disorders, such as Phelan-McDermid syndrome, Fragile X and Tuberous Sclerosis, might be of significant help since the neurobiology of these disorders is clearer and clinical trials are already underway for these conditions. The pathogenesis paradigm shift of ASD towards synaptic abnormalities has led to current research of the pathways to disease, which involves multiple dynamic systems. Interest in oxytocin is growing as it has been recognized to be implicated in social development and affiliative behaviours. In the future, progress is expected in possible new options for therapeutics in ASD. Children and adolescents with ASD and their families can provide vital information about their experiences with new treatments, which should be a priority for future research.

Abstract Earlier identification and diagnosis of autism spectrum disorders (ASDs) can improve opportunities for children to benefit from intervention and lessen the burden on concerned parents. This review summarizes current knowledge about early signs of autism. Convergent data from both retrospective studies and prospective studies of high-risk infants indicate that ASD symptoms emerge in the first two years of life, affecting multiple developmental domains, mapping onto symptom dimensions consistent with current diagnostic frameworks including social-communication, and repetitive interests/behaviors but also extending to motor delays and atypical regulation of attention and emotion. Recent findings have shed new light on patterns of symptom onset and progression, and promise to inform early detection and diagnosis. Further attention to effective application of new findings and related challenges in building health system capacity to ensure timely access to specialized assessment and interventions is needed to fully realize the promise of improved outcomes resulting from this research.

A popular idea related to early brain development in autism is that a lack of attention to, or interest in, social stimuli early in life interferes with the emergence of social brain networks mediating the typical development of socio-communicative skills. Compelling as it is, this developmental account has proved difficult to verify empirically because autism is typically diagnosed in toddlerhood, after this process of brain specialization is well underway. Using a prospective study, we directly tested the integrity of social orienting mechanisms in infants at-risk for autism by virtue of having an older diagnosed sibling. Contrary to previous accounts, infants who later develop autism exhibit a clear orienting response to faces that are embedded within an array of distractors. Nevertheless, infants at-risk for autism as a group, and irrespective of their subsequent outcomes, had a greater tendency to select and sustain attention to faces. This pattern suggests that interactions among multiple social and attentional brain systems over the first two years give rise to variable pathways in infants at-risk.

Face processing is a neural mechanism that allows understanding social information and cues conveyed by faces, whose dysfunction has been postulated to underlie some of the behavioral impairments characterizing Autism Spectrum Disorders (ASD). A special region of the cortex, the Fusiform Gyrus (FG), is believed to be the specific area for processing face features and emotions. However, behavioral, fMRI and ERP studies addressed to investigate the role of FG dysfunction in ASD have led to conflicting results. Using a high-density EEG system, we recorded the face-sensitive ERP to neutral and emotional (happiness and fearful) faces, as a measure of early activity of the FG, in children with high functioning ASD. By controlling a number of experimental and clinical variables that could have biased previous research – such as gaze direction, attention to tasks, stimulus appearance and clinical profiles – we aimed to assess the effective role of the FG in the face emotion processing deficit hypothesized in ASD. No significant differences in early face-sensitive ERP components were found between ASD and neurotypical children. However, a systematic latency delay and amplitude reduction of all early potentials were observed in the ASD group, regardless of the stimulus, although more evident for emotions. Therefore, we can assume a diffuse dysfunction of neural mechanisms and networks in driving and integrating social information conveyed by faces, in particular when emotions are involved, rather than a specific impairment of the FG-related face processing circuit. Nevertheless, there is need of further investigation.

Abstract Research has demonstrated the potential role of the brainstem in the pathobiology of autism. Previous studies have suggested reductions in brainstem volume and a relationship between this structure and sensory abnormalities. However, little is known regarding the developmental aspects of the brainstem across childhood and adolescence. The goal of this pilot study was to examine brainstem development via MRI volumetry using a longitudinal research design. Participants included 23 boys with autism and 23 matched controls (age range = 8–17 years), all without intellectual disability. Participants underwent structural MRI scans once at baseline and again at two-year follow-up. Brainstem volumetric measurements were performed using the BRAINS2 software package. There were no significant group differences in age, gender, handedness, and total brain volume ; however, full-scale IQ was higher in controls. Autism and control groups showed different patterns of growth in brainstem volume. While whole brainstem volume remained stable in controls over the two-year period, the autism group showed increases with age reaching volumes comparable to controls by age 15 years. This increase of whole brainstem volume was primarily driven by bilateral increases in gray matter volume. Findings from this preliminary study are suggestive of developmental brainstem abnormalities in autism primarily involving gray matter structures. These findings are consistent with autism being conceptualized as a neurodevelopmental disorder with alterations in brain-growth trajectories. More longitudinal MRI studies are needed integrating longitudinal cognitive/behavioral data to confirm and elucidate the clinical significance of these atypical growth patterns.

Abstract Individuals with autism spectrum disorder (ASD) show impairments in processing coherent motion which have been proposed to be linked to a general deficit in the dorsal visual pathway. However, few studies have investigated the neural mechanisms underlying coherent motion processing in ASD. Thus, the aim of this study was to further test the hypothesis of a dorsal pathway deficit in ASD using visual evoked potentials (VEPs). 16 children and adolescents with ASD and 12 typically developing controls were examined with VEPs elicited by a random dot kinematogram. After an initial experimental sequence, where subjects were presented randomly moving dots, a fraction of the dots moved coherently (dependent on the level of coherence, 20%, 40%, or 60% of the dots) to the left or right side. Subjects were asked to detect the direction of coherent motion via button press. On the behavioural level, no significant group differences emerged. On the neural level, coherently moving dots elicited a N200 followed by a late positive potential (P400). ASD subjects exhibited a reduced N200 amplitude compared to controls. Moreover, in the ASD group, a trend for a negative relationship between N200 amplitude and a measure of autistic pathology was revealed. The present study provides strong support of a dorsal stream deficiency in the disorder and renders alternative explanations for impaired coherent motion processing in ASD less likely. Together with findings from related research fields, our data indicate that deviances in the N200 during coherent motion perception might be fundamental to ASD.

Abstract This research focuses on the impact of emotions – defined as “motivational states” – on the organization of goal directed locomotion in children with autism. Walking toward a goal involves both cognitive processes responsible for movement planning and automatic processes linked to movement programming. To these processes, motivation leading to achieving the goal is added. For some authors, a deficit of planning and/or programming processes is highlighted in autism. Others stand for some impairment of the emotional system. The aim of this research is to link these two viewpoints and to determine if, in children with autism, the organization of locomotion is affected by a positive/aversive emotion conferred to an object to fetch. Twenty-nine children participated in the study (11 children with autism – mean age 122 months ; 9 mental age-matched controls – mean age 36 months ; and 9 chronological age-matched controls – mean age 122 months). They were instructed to go and get a positive or aversive emotional valence object located straight ahead, at 30° to the right or straight ahead then moved at mid-distance to the right. Gait analysis was performed using the Vicon system. The main results suggest that a positive emotional context promotes the cognitive processes involved in movement planning while an aversive emotional context blocks it or disturbs it in children with autism. No emotions effect is observed on movement programming. It is suggested that emotions triggered off and modulated movement planning and that the deficit observed was related to a developmental impairment rather than to a developmental delay.